Drug abuse is a debilitating psychiatric illness with few effective treatments. In particular, there are no generally accepted or FDA approved pharmacotherapies for cocaine addiction. One promising form of treatment is physical exercise, which has been shown in small pilot studies to reduce the incidence of relapse in subjects participating in traditional drug treatment programs. Similarly, rats that engage in chronic voluntary wheel running exhibit a significantly lower rate of drug-seeking behavior compared to sedentary counterparts in the reinstatement model of relapse. However, the mechanism by which how exercise mediates its therapeutic effects on relapse is not known. We have shown previously that chronic exercise increases galanin mRNA expression specifically in the locus coeruleus (LC), the major brainstem noradrenergic nucleus that supplies NE to the forebrain. Galanin peptide is a potent endogenous inhibitor of LC activity, and chronic exercise attenuates NE release. Because NE transmission is critical for reinstatement of cocaine seeking in rats, galanin provides a potential mechanistic link through which chronic exercise could influence reinstatement of drug seeking. Specifically, we hypothesize that chronic exercise attenuates the reinstatement of cocaine seeking by increasing galanin in the LC, which then suppresses NE release. In Specific Aim 1, I will use in situ hybridization, RT-PCR, western blot, and behavioral pharmacology to determine whether (1) chronic voluntary exercise increases galanin mRNA and peptide in the LC of rats with a history of cocaine self-administration, (2) direct activation of galanin receptors can mimic the effects of exercise on reinstatement of cocaine seeking in sedentary rats, and (3) blockade of galanin receptors can attenuate the effects of chronic exercise on cocaine seeking. In Specific Aim 2, I will use in vivo microdialysis to determine whether chronic voluntary exercise attenuates cocaine-induced NE release in a galanin-dependent manner in rats with a history of cocaine self-administration. This study will provide new insight into the neurobiology of cocaine dependence and potential addiction therapies by investigating the interaction between relapse-like behavior, exercise and galanin. Understanding the mechanism by which exercise attenuates relapse will help confirm and optimize the therapeutic effects of exercise in drug-dependent individuals, and may identify novel targets for cocaine addiction pharmacotherapies. PUBLIC HEALTH RELEVANCE: Drug addiction is a complex psychiatric illness that requires multifaceted approaches of treatment. In particular, there are currently no generally accepted, effective therapies for cocaine addiction. Although the addition of a physical exercise regimen to traditional treatment programs has been shown to significantly reduce the incidence of relapse, the neural basis underlying these therapeutic effects are unknown. Understanding these mechanisms will provide a novel tool for treating cocaine addiction, identify neural targets for novel pharmacotherapies, and provide new insight on the neurobiology of drug addiction.